The present invention is related to novel compounds of formula (I) that inhibit the activity of the FabI enzyme which are therefore useful in the treatment of bacterial infections. It further relates to pharmaceutical compositions comprising these compounds, and chemical processes for preparing these compounds.
The compounds of the present invention are antibacterial compounds that inhibit the FabI protein, a NADH-dependent enoyl-acyl carrier protein (ACP) reductase enzyme in the fatty acid biosynthesis pathway. Fatty acid synthase (FAS) is involved in the overall biosynthetic pathway of saturated fatty acids in all organisms, but the structural organization of FAS varies considerably among them. The distinctive characteristics of FAS of vertebrates and yeasts are that all enzymatic activities are encoded on one or two polypeptide chains, and that the acyl carrier protein (ACP) exists in the form of a complex. In contrast, in bacterial FAS, each of synthetic steps is catalyzed by a distinct, mono-functional enzyme and the ACP is a discrete protein. Therefore, it is possible to selectively inhibit bacterial FAS by blocking one of the synthetic steps using an inhibitory agent. NADH-dependent enoyl-ACP reductase (Fab I) is involved in the last step of the four reaction steps involved in each cycle of bacterial fatty acid biosynthesis. Thus, the FabI enzyme is the biosynthetic enzyme in the overall synthetic pathway of bacterial fatty acid biosynthesis.
The FabI enzyme has been shown to constitute an essential target in major pathogens such as E. Coli (Heath et al. J. Biol. Chem. 1995, 270, 26538; Bergler et al. Eur. J. Biochem. 2000, 275, 4654). Hence, compounds that inhibit FabI may be useful as antibacterials.
Compounds having FabI enzyme inhibitory activity have been disclosed in WO-01/26652, WO-01/26654, and WO-01/27103. Substituted naphthyridinone compounds having FabI inhibitory activity have been disclosed in WO-03/088897, WO-2007/043835 and WO-2008/098374. International patent application WO 2007/053131 also discloses various naphthyridone compounds for potential use as FabI inhibitors. However, none of these documents discloses a compound in which there is a cyclic amino group directly attached to a carbonyl moiety that is a to an alkene. International patent application WO 2011/061214 also discloses various compounds for potential use as FabI inhibitors. However, this document does not disclose inter alia compounds in which there is a nitrogen-containing cyclic group containing a double bond or an additional nitrogen heteroatom.